KR20170062041A - Method and apparatus for microfluidic chip filtration using controlled ionic concentration in solution - Google Patents

Method and apparatus for microfluidic chip filtration using controlled ionic concentration in solution Download PDF

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KR20170062041A
KR20170062041A KR1020150167388A KR20150167388A KR20170062041A KR 20170062041 A KR20170062041 A KR 20170062041A KR 1020150167388 A KR1020150167388 A KR 1020150167388A KR 20150167388 A KR20150167388 A KR 20150167388A KR 20170062041 A KR20170062041 A KR 20170062041A
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ion concentration
channel
main channel
particles
double layer
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KR101758826B1 (en
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전명석
전영민
김재헌
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한국과학기술연구원
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C5/00—Separating dispersed particles from liquids by electrostatic effect

Abstract

A method for filtrating a microfluidic chip comprises injecting a sample fluid having particles and an electrolyte and having a first ion concentration into a main channel; Injecting a solvent solution into the side channel connected to the first side of the main channel, the solvent solution having an electrolyte and a second ion concentration lower than the first ion concentration; And withdrawing the particles from the main channel to one or more branch channels connected to a second side of the main channel different from the first side by the solvent liquid. By making the ion concentration of the side flow relatively low and the ion concentration of the main flow relatively high, a thick electrical double layer is formed on the side flow wall surface to the main channel outlet, The separation efficiency can be improved.

Description

Technical Field [0001] The present invention relates to a microfluidic chip filtration method and apparatus using microfluidic chip filtration,

Embodiments relate to a microfluidic chip filtering apparatus and method using a multiple branch channel and more particularly to a microfluidic chip filtering apparatus and method using a hydraulic flow The present invention relates to a microfluidic chip filtration method and apparatus for improving separation efficiency by regulating the ion concentration of a sample fluid as a main flow and a solvent fluid as a side flow in hydrodynamic filtration.

There is a method of hydrolytic filtration and separation by inertial force as a method of manipulating and separating particles and cells by hydrodynamic effects in a channel flow without voluntary introduction of external fields such as magnetic field, dielectrophoresis, and optical techniques . Hydraulic filtration is based on the flow resistance to laminar flow and the flow fraction at any channel point. Numerous studies and developments have been made on various types of cells for hydrodynamic filtration. For example, in Japanese Patent Laid-Open Publication No. 2012-076016, entitled " Apparatus and Method for Continuous Two- .

1 is a plan view of an apparatus for showing the principle of a conventional hydraulic filtration apparatus.

Referring to FIG. 1, in the conventional hydrodynamic filtration apparatus, when a sample liquid in which particles or cells are dispersed is continuously introduced into the main channel 10 and flows, the flow fraction in each branch channel 30 Separation occurs by selective exclusion of the streamline as determined by. In FIG. 1, the branch channel 30 is shown as one channel, but in practice it is a multiple straight line channel consisting of many. In order to enhance the flow fractionation effect, a solvent medium is continuously introduced into a side channel 20 connected to the side surface of the main channel 10 so that the sample liquid is supplied to the main channel 10 opposite to the side channel 20 ) To the wall. The stream line near the wall surface where the branch channel 30 is formed in the main channel 10 falls into the branch channel 30. At this time, the particles whose center is located in the stream line also fall into the branch channel 30. [ The flow rate exiting the branch channel 30 is determined from the flow distribution between the main channel 10 and the branch channel 30 in relation to the flow resistance in the channel network.

In FIG. 1, W C is a cut-off thickness formed by this flow distribution, and it is determined whether or not the particle falls into the branch channel 30 according to the size of W C and the radius of the particle. The width of the main channel 10 is W, the flow rate at the inlet of the main channel 10 is

Figure pat00001
, The flow rate at the inlet of the side channel (20)
Figure pat00002
, The flow rate for the range satisfying W / 2-W C = X with respect to the range of -X? X? 0 (or symmetry, 0? X ? X )
Figure pat00003
+
Figure pat00004
= Q and
Figure pat00005
+ Q X = Q / 2. Therefore, the flow ratio at the branching point S b at which the branch channel 30 branches from the main channel 10 is determined by the following equation (1).

Figure pat00006

Here, the flow rate is obtained by integrating the velocity distribution obtained by the equation of motion and the boundary condition for the channel section in a normal state and laminar Newtonian fluid in a quadrangular square channel section.

In the hydrodynamic filtration method, the branch channels are generally formed in a number of tens or more in order to enhance the flow focusing effect, and they are collected at the outlet portion and discharged to the outside. Here, the outlet is designed to be installed as many as the number of aliquots to be separated by a specific size in a sample solution in which particles or cells are mixed in various sizes. The flow rate ratio between the branch channel and the main channel at the branch point to any j-th branch channel among the channel networks having dozens of branch channels can be summarized as shown in Equation (2).

Figure pat00007

In the above Equation 2,

Figure pat00008
= tanh (npW / 2H),
Figure pat00009
= cosh (npW / 2H),
Figure pat00010
= sinh (npX / H), and W and H indicate the width and height of the main channel, respectively. From the relationship between the pressure drop at each point and the above equation (2), the W C value set for separating the desired particles or cells and the width, height, length, and number of branch channels of each channel, In order to determine all design values such as the number of outlets, complex iterations must be performed.

However, even when designing channels with design values derived from accurate calculations, separation efficiency may be degraded if disturbances occur in flow alignment and particle alignment.

2A and 2B show the above separation efficiency deterioration phenomenon, wherein FIG. 2A is a plan view showing a device configuration having N branch channels collected at one outlet for separating bi-dispersed particles, FIG. FIG. 5 is a plan view showing a device configuration with N and M branch channels each collected at two outlets for tridisperse particle separation. FIG. Here, N and M are arbitrary natural numbers.

As shown in FIGS. 2A and 2B, when the particles are out of the thickness (W C1 and W C2 ) of the cutoff layer, particles of a desired size are not separated into a given branch channel and the particles flow into the main channel, . The particles 200 indicated by arrows in Figures 2a and 2b represent particles that have not been separated into the desired branch channel. This can be further exacerbated in the polydisperse particle separation where the thickness of the cutoff layer increases toward the second half of the main channel.

Japanese Laid-Open Patent Publication No. 2012-076016

According to one aspect of the present invention, the hydrodynamic filtration by the flow fraction of the main channel and the branch channel allows the particle alignment to be maintained over the entire length of the main channel And the target particles can be accurately separated by a given branch channel.

According to one embodiment, a method for filtering a microfluidic chip includes injecting a sample solution containing particles and an electrolyte and having a first ion concentration into a main channel; Injecting a solvent solution into the side channel connected to the first side of the main channel, the solvent solution having an electrolyte and a second ion concentration lower than the first ion concentration; And withdrawing the particles from the main channel to one or more branch channels connected to a second side of the main channel different from the first side by the solvent liquid.

The method for filtrating microfluidic chips according to an embodiment further includes adjusting a thickness of an electric double layer formed on a wall surface of the main channel using the first ion concentration and the second ion concentration.

In one embodiment, adjusting the thickness of the electric double layer is configured to adjust the thickness of the electric double layer formed on the second side of the main channel and the wall surface of the branch channel using the first ion concentration . In one embodiment, the step of adjusting the thickness of the electric double layer is configured to adjust the thickness of the electric double layer formed on the first side of the main channel using the second ion concentration.

A microfluidic chip filtering apparatus according to an embodiment includes a main channel configured to flow a sample solution containing particles and an electrolyte; A side channel connected to the first side of the main channel, the side channel concentrating the sample solution to the second side of the main channel by injecting a solvent solution containing the electrolyte; And one or more branch channels connected to a second side of the main channel and configured to allow the particles to escape from the main channel. At this time, the sample liquid has a first ion concentration, and the solvent liquid has a second ion concentration lower than the first ion concentration.

In one embodiment, the microfluidic chip filtering apparatus further comprises an electrical double layer formed on the wall surface of the main channel by ions generated by dissociation of the electrolyte and having a thickness determined by the first ion concentration and the second ion concentration .

In one embodiment, the electrical double layer comprises a layer formed on the second side of the main channel and the wall surface of the branch channel, the thickness being determined by the first ion concentration. In one embodiment, the electric double layer further comprises a layer formed on the first side of the main channel and having a thickness determined by the second ion concentration.

In one embodiment, each of the main channel, the side channel, and the one or more branch channels has a shape in which the height of the channel is larger than the width.

In the microfluidic chip filtration method and apparatus according to an embodiment, the first ion concentration is 10 4 to 10 6 times the second ion concentration.

In one embodiment, the first ion concentration is from 10 mM to 100 mM. In one embodiment, the second ion concentration is from 10 -4 mM to 10 -1 mM.

In one embodiment, the electrolyte comprises a cation and an anion dissociated in a ratio of 1: 1.

A microfluidic chip according to an embodiment includes: a first substrate; A main channel formed on the first substrate and configured to flow a sample solution including particles and an electrolyte; A side channel connected to the first side of the main channel, the side channel concentrating the sample solution to the second side of the main channel by injecting a solvent solution containing the electrolyte; And at least one branch channel connected to a second side of the main channel and configured to allow the particles to escape from the main channel; And a second substrate bonded to a surface of the first substrate on which the microfluidic chip filtering apparatus is formed. At this time, the sample liquid has a first ion concentration, and the solvent liquid has a second ion concentration lower than the first ion concentration.

According to one aspect of the present invention, a microfluidic chip filtration method and apparatus are capable of performing hydrodynamic filtration by a flow fraction between a main channel and a branch channel, ) To the outlet of the main channel to form a thick electrical double layer on the wall surface to prevent disturbance in particle alignment. As a result, there is an advantage that separation efficiency of polydisperse particles can be improved without applying expensive equipment or complicated processes. Furthermore, in addition to the effect of improving the separation efficiency, the application of the electrostatic repulsion principle also has an advantage in that the lifetime of the channel is prolonged because particles are not adsorbed from the channel wall, which is a factor that clogs the channel.

Figure 1 is a top view of a simple device for illustrating the principle of a conventional hydrodynamic filtration device.
2a and 2b are plan views showing that the separation efficiency is lowered due to disturbance of particle alignment at the rear main flow wall surface in a conventional hydrodynamic filtration apparatus for two dispersed and tridisperse particles.
FIGS. 3A and 3B are diagrams showing changes in the thickness of the electric double layer formed around the charged channel wall surface in accordance with the ion concentration of the solution. FIG.
4A and 4B are graphs showing the degree of the particle approaching the channel wall surface depending on the electric double layer thickness formed around the charged channel wall surface and the chargeability of the particles according to the ion concentration of the solution.
5a to 5d are plan views showing the behavior of particles according to the ion concentration of a sample solution as a main flow solution and a solvent solution as a side flow solution in a microfluidic chip filtration device for hydrodynamic filtration of three dispersed particles.
6 is a view showing a structure of a microfluidic chip implementing hydrodynamic filtration according to an embodiment.
7 is a photograph of a microfluidic chip according to an embodiment.
FIG. 8A is a graph showing the recovery rate for the separation of three dispersed particles by the conventional hydrodynamic filtration method. FIG.
FIG. 8B is a graph showing the purity of separation of three dispersed particles by the conventional hydrodynamic filtration method. FIG.
FIG. 9A is a graph showing recovery rates for separation of three dispersed particles by size according to one embodiment of a microfluidic chip filtration method. FIG.
FIG. 9B is a graph showing the purity of separation of three dispersed particles by the microfluidic chip filtration method according to one embodiment. FIG.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.

Hydrodynamic filtration is based on the principle of flow resistance against laminar flow and flow fractionation at arbitrary channel points. The device for realizing this is one or a plurality of channels connected to the main channel and the main channel Branch channels are installed. In addition, a side channel for injecting a solvent solution for forming a cut-off layer for filtering the particles of a specific size dispersed in the sample liquid into the main channel is installed .

The plurality of branch channels are for increasing the particle sorting effect by flow sorting. In order to separate the particles, particles dispersed in the sample liquid introduced into the main flow are separated by a side flow in the main channel Maintain the behavior located on the main flow wall near the branch channel. As used herein, the term "side flow wall surface" refers to a wall surface of a side surface to which a side channel is connected in a main channel, and "main flow wall surface" Side walls).

However, the lateral flow intensity becomes weaker in the two-dispersed particle separation toward the latter half of the main channel, and in the case of particle separation of three or more dispersions, the thickness of the cutoff layer becomes larger and the role of the lateral flow is lowered, have. When such a disturbance of particle alignment occurs, the center of the particle is deviated from the thickness of the set cutoff layer and flows along the main channel without falling into the branch channel through which the particle should escape. As a result, the desired hydrodynamic filtration can not be realized, there is a problem. In particular, this problem is more pronounced in polydisperse particle separations above tridisperse.

Embodiments of the present invention solve the above-described problems and utilize the electrostatic repulsion force between the charged channel wall surface and the particles to keep the particles positioned near the main flow wall surface. The sample liquid and the solvent liquid contain a large number of ions generated by dissociation of the electrolyte. An electric double layer is formed around the channel walls charged by these ions, so that an electrostatic repulsion force acts. Since the electric double layer changes its thickness depending on the ion concentration of the solution, if an electric double layer of appropriate thickness is formed around the side flow wall surface of the main channel by adjusting the ion concentration, the particles dispersed in the sample solution are positioned near the main flow wall surface The filtration into the branch channels can be made as designed while maintaining the particle focusing to improve the separation efficiency.

In order to generate an electrostatic repulsion force, the channel wall surface may be made of polydimethylsiloxane (PDMS), glass, silicon, quartz or other suitable material widely used as a material of a microfluidic chip. When such a negatively charged solid wall is brought into contact with a solution containing an electrolyte such as water, the electrolyte dissociates and the generated positive ions are gathered around the solid wall. The microfluidic chip filtration method according to the embodiments may be performed by using a micro total analysis system such as sorting, counting, and fractionation of particles having a size of about 10 mm or less, for example, ). ≪ / RTI > The particles described herein may include vesicles, polysaccharides, various cells, and the like, as well as particles whose shape is unchanged.

FIGS. 3A and 3B are diagrams showing changes in electric double layer thickness formed around a charged channel wall surface according to ion concentration of a solution, in order to explain the principle of particle separation according to embodiments of the present invention. FIG. FIG. 3A shows the case where the ion concentration of the solution is relatively high, and FIG. 3B shows the case where the ion concentration of the solution is relatively low. Generally, a low ionic concentration of 10-1 mM or less and a high ionic concentration of 10 mM or more can be defined.

Referring to FIG. 3A, when the ion concentration of the electrolyte contained in the solution is high, a sufficient number of positive ions enclose a negative charge on the solid wall surface, and the chargeability of the solid wall surface is weakened. On the other hand, referring to FIG. 3B, if the ion concentration of the electrolyte contained in the solution is low, a small number of positive ions enclose a negative charge on the solid wall surface, so that the chargeability of the solid wall surface will not be significantly weakened. The area up to the distance where the charge effect of the solid wall is remarkable is called the electric double layer. When the ion concentration of the solution is low, the electric double layer becomes thicker as compared with FIGS. 3A and 3B.

The inside of the channel is divided into an electric double layer region in which ions opposite to the charges on the solid wall face exist predominantly and an electrically neutral bulk region in which positive ions and negative ions exist in the same number. In a situation where the solution continues to flow into the channel, even if a specific ion is unevenly distributed in the electric double layer, there are a myriad of positive ions and anions in the bulk region. Therefore, the ion concentration in the bulk region is, Speak. Here, the thickness of the electric double layer is generally denoted by κ -1 , and is defined as follows.

Figure pat00011

In Equation (3), n b represents the ion concentration of the solution in the bulk region, Z i represents the ion valence of the i ion, e represents the unit charge of 1.6 × 10 -19 Coul, Boltzmann) shows thermal energy. Also, e is a dielectric constant, which is the product of the relative permittivity and the dielectric constant in vacuum, and is e = (79) × (8.854 × 10 -12 ) Coul 2 / J · m at room temperature. Here, it is assumed that the sample liquid in which the particles are dispersed usually has a relative permittivity and a viscosity at the same level as that of water. For example, the relative dielectric constant of the sample liquid is 79 at room temperature, and the viscosity may be 1.0 × 10 -3 kg / m · sec.

In one embodiment, the electrolyte dissolved in the sample solution is a material in which cations and anions are dissociated at a ratio of 1: 1, such as potassium chloride (KCl) and sodium chloride (NaCl). In this case, the electric double layer thickness κ -1 having nm units can be simply calculated as shown in the following equation (4).

Figure pat00012

Table 1 below shows the thickness of the electric double layer according to the ion concentration of the electrolyte. The thickness of the electric double layer is calculated by changing the ion concentration of the solution from the lowest ion concentration limit of 10 -4 mM to the highest limit of 100 mM. It is.

The ion concentration of the solution, C b (mM) Electrical double layer (EDL) thickness, κ -1 (nm) 10 -4 (deionized and secondary distilled water) 965 10 -3 305 10 -2 96.5 10 -1 30.5 1.0 9.7 10 3.1 100 (high concentration limit) 0.97

In Table 1 above, the ion concentration C b is defined by n b (1 / m 3 ) = N A × C b based on the ion concentration in the bulk region, where N A is Avogadro's number.

Referring to Table 1, when the ion concentration is increased by 100 times, the electric double layer thickness is decreased by 10 times. Generally, a lower ion concentration is defined as 10 -1 mM or less, and a higher ion concentration is defined as 10 mM or higher. Preferably, a sufficiently low ion concentration of 10 < -3 > mM or less determines the exact ion concentration by the conductivity value of the sample solution.

Meanwhile, the difference between the high ion concentration and the low ion concentration defined in one embodiment of the present invention is 10 4 to 10 6 times, and as a result, the electric double layer thickness varies by 100 to 1,000 times depending on the ion concentration difference. For example, if the ionic concentration difference 10 four times in 10 mM and 10 mM, respectively -3 high ionic concentration and low ionic concentration, the electrical double layer thickness of the fly 100-fold difference, respectively 3.1 nm and 305 nm.

4A and 4B are graphs showing the degree of approach of the particles to the channel wall surface depending on the thickness of the electric double layer formed around the charged channel wall surface and the chargeability of the particles according to the ion concentration of the solution, And FIG. 4B shows a case where the ion concentration of the solution is low. A high ion concentration and a low ion concentration are defined as described above with respect to FIG.

4A and 4B, the approach distance between the channel wall surface and the particle is determined by the electric double layer thickness and the chargeability of the particles. The non-charged particles 401 are the maximum approach distance of the electric double layer thickness formed around the channel walls. Also, the charge-charged particles 402 (e.g., anionic wall surface and anionic particles), such as charge on the channel wall surface, can have a maximum electrical double layer thickness formed around the channel walls and particles by electrostatic repulsion It is approach distance. On the other hand, electrostatic attraction is applied to the charged particles 403 charged to the opposite side of the channel wall surface, so that the charged particles 403 can contact the channel wall surface as opposed to the charge on the channel wall surface.

Embodiments of the present invention can adjust the ion concentration of each of the sample liquid, which is the main flow in the hydrodynamic filtration, and the solvent liquid, which is the side flow, from the above-described relationship, so that both side walls of the main channel ) And the electrical double layer thickness formed on the branch channel walls.

5a to 5d are plan views showing the behavior of particles according to the ion concentration of the main flow solution and the side flow solution in the microfluidic chip filtration device for the hydrodynamic filtration of the three dispersion particles.

The microfluidic chip filtering apparatus includes a main channel 10, a side channel 20 connected to the first side of the main channel 10 and one or more branch channels 41 and 42 connected to the second side of the main channel 10 . For example, the first side and the second side may be opposite sides. At this time, the wall surface of the main channel 10 in which the branch channels 41 and 42 are located corresponds to the main flow wall surface 110 and the wall surface of the main channel 10 in which the side channel 20 is located is the side flow wall surface 120 ).

Although each channel 10, 20, 41, 42 in the drawings herein is shown as a component having a predetermined shape, each channel 10, 20, 41, (Not shown), such as a substrate, and each channel 10, 20, 41, 42 shown in the figure represents the shape of such a space It is intended. The substrate, such as a substrate, may be made of PDMS which facilitates processing of a channel having a desired shape, but is not limited thereto.

The main channel 10 is a space through which a sample solution containing particles to be filtered flows. In the present specification, the term "particle" is intended to encompass not only particles that do not change in shape, such as nanoparticles, but also vesicles, polysaccharides, and various cells that change in shape, and are not limited to specific types. The sample liquid flowing in the main channel 10 may include one or more kinds of particles 101-103 having different sizes and a part or all of the particles 101-103 may be supplied from the main channel 10 to the branch channels 41, 42, so that the particles can be filtered through the branch channels 41, 42.

The side channel 20 is connected to the second side 120 of the main channel 10 to continuously introduce the solvent 101 to the main flow wall surface 110 opposite the side channel 20 by continuously introducing solvent medium, 103 in the direction of the arrow. In one embodiment, the side channel 20 is connected to the main channel 10 at an angle of 60 degrees with the main channel 10, but is not limited thereto.

The branch channels 41 and 42 are formed in the wall surface opposite the side channel 20 in the main channel 10 and are formed so that one or more branch channels 41 and 42 are connected to one outlet. The widths W B1 and W B2 of the branch channels 41 and 42 are equal to or smaller than the width W of the main channel 10. The stream lines near the wall surface 110 where the branch channels 41 and 42 are formed in the main channel 10 fall into the branch channels 41 and 42. At this time, (41, 42). The flow rate exiting the branch channels 41 and 42 is determined from the flow distribution between the main channel 10 and the branch channels 41 and 42 in relation to the flow resistance in the channel network, The thicknesses W C1 and W C2 of the cut-off layer formed at the branch points corresponding to the channels 41 and 42 and the radius of the particles 101-103 cause the particles to pass through the branch channels 41 and 42 Is determined.

The number of branch channels (41, 42) is determined by the number of outlets through which the aliquot to be separated is discharged according to a specific size in the sample liquid in which the particles are mixed in various sizes. In Fig. 5, three kinds of particles 101-103 of different sizes and branch channels 41 and 42 connected to two outlets for separation thereof are shown in order to illustrate the separation process of three dispersed particles. However, it is to be understood that the number of particles contained in the sample liquid to be filtered by the microfluidic chip filtering apparatus according to the embodiments may be smaller or larger, Can be different.

In one embodiment, each of the main channel 10 and the branch channels 41 and 42 has a shape in which the height of each channel is larger than the width, that is, the aspect ratio of the channel cross-section is small. It should also be understood that the shape and size of each channel 10, 20, 41, 42 shown in Fig. 5 is merely exemplary and does not limit the actual shape and size of each channel.

FIG. 5A shows the application of conventional hydrodynamic filtration conditions to the microfluidic chip filtration apparatus constructed as described above, wherein the ion concentration of both the sample solution and the solvent solution is set to a high ion concentration, for example, 10 mM to 100 mM . As a result, a thin electric double layer is formed on both side walls 110 and 120 of the main channel 10 and on the wall surfaces of the branch channels 41 and 42 so that the front part of the main channel 10 (I.e., a portion relatively adjacent to the injecting portion of the sample liquid), the particles are positioned on the main flow wall surface 110, but the role of the side flow becomes smaller toward the latter half of the main channel 10 It is weakened. In addition, in the case of three or more dispersed particles, the thicknesses (W C1 , W C2 ) of the cut-off layer become larger toward the latter half of the main channel 10 so that the particles 101-103 deviate from the main flow wall surface 110, Can be disturbed, which results in particles not being separated into the desired branch channels 41, 42.

On the other hand, FIG. 5B shows that the ion concentrations of both the sample solution and the solvent solution are low, for example, 10 -4 mM to 10 -1 mM. 5B, when the ion concentrations of the sample liquid and the solvent liquid are both lowered, a thick electric double layer is formed on both side walls 110 and 120 of the main channel 10, (101-103) are aligned with the center of the channel, separation of the particles (101-103) can not be normally performed. Moreover, the thick electrical double layer formed on the wall surfaces of the branch channels 41, 42 prevents particles from escaping from the main channel 10 to the branch channels 41, 42.

5C is a graph showing the relationship between the ion concentration of the sample liquid supplied to the main channel 10 and the ion concentration of the solvent liquid supplied to the side channel 20, Represents a case where the second ion concentration is relatively low. For example, the first ion concentration may be 10 4 to 10 6 times the second ion concentration. Also, the first ion concentration may be from 10 mM to 100 mM. Further, the second ion concentration may be 10 -4 mM to 10 -1 mM. As a result of the adjustment of the ion concentration as described above, disturbance of the particle alignment at the rear half of the main channel 10 described above with reference to FIG. 5A is suppressed by the thick electric double layer formed on the side flow wall surface, / RTI >

Conversely, when the ion concentration of the solvent liquid supplied to the side channel 20 is increased and the ion concentration of the sample liquid supplied to the main channel 10 is lowered as shown in FIG. 5D, A thick electrical double layer formed on the wall surfaces of the branch channels 41 and 42 as in Fig. 5b causes particles to flow from the main channel 10 to the branch channels 41 , 42).

In the case of FIG. 5A, which is a conventional hydrodynamic filtration condition, the separation efficiency is limited. In the case of FIGS. 5B and 5D in which the ion concentrations of the sample solution and the solvent solution are both low or high, they are not suitable for hydrodynamic filtration . As a result, the separation efficiency can be maximized by the hydrodynamic filtration conditions according to the embodiment of the present invention described above with reference to FIG. 5C.

FIG. 6 is a view showing a structure of a microfluidic chip including the microfluidic chip filtration device described above with reference to FIG. 5C and implementing the hydrodynamic filtration.

Figure 6 shows that for performing separation using a small particle (D S), the median particle (D M), and large particles (D L) The microfluidic chip according to the present embodiment with respect to the mixture 3 dispersed particles. Here, the size of particles is defined as relative to other kinds of particles, and is not limited to a specific value. Referring to FIG. 6, at the point where the thickness (W C1 ) of the cutoff layer is set, the D S particles fall into the branch channel 41 connected to the outlet 1, while the D M and D L particles fall into the main channel 10 It flows along. Thereafter, at a point where the thickness (W C2 ) of the cutoff layer is set, the D M particles fall into the branch channel 42 connected to the outlet 2 while the D L particles flow along the main channel 10 to the main channel 10 Connected outlet 3. By the above process, each of D S , D M and D L particles can be separated.

7 is a photograph of a microfluidic chip according to an embodiment.

The material of the microfluidic chip according to the embodiments may be PDMS, glass, silicon, quartz, or the like. In the manufacturing process, channels can be formed on a first substrate made of PDMS or the like by a micro-electro-mechanical system (MEMS) process or the like. At this time, the main channel inlet, the side channel inlet, the outlet through which the branch channels are collected, and the main channel outlet may be formed by penetrating the first substrate with a circular knife, but the present invention is not limited thereto. The diameter of each inlet and outlet formed may be 1/16 inch to enable the tubing to be installed, but is not limited thereto and can be appropriately adjusted according to the diameter of the tubing. The microfluidic chip can be manufactured by bonding the first substrate with the second substrate. The second substrate may be bonded to the surface of the first substrate on which the channel is formed by oxygen plasma bonding, but the present invention is not limited thereto.

In one embodiment, the width of the main channel and the side channel is at least 1.5 times the diameter of the largest diameter particle among the particles dispersed in the sample liquid. Also, in one embodiment, the width of each branch channel is 1.5 to 3 times the diameter of the particles that will pass through that branch channel. Also, in one embodiment, the channel width can be from about 1 to 15 micrometers (μm), whichever channel it is. In one embodiment, the height of each channel is greater than the channel width.

In one embodiment, the thickness of the first substrate is 1.5 to 2.5 mm. In one embodiment, the width of the second substrate, which is the lower substrate, is larger than that of the first substrate on the upper side. The thickness of the second substrate is 1.0 to 1.5 mm. In one embodiment, the first substrate is made of PDMS and the second substrate is made of glass.

As shown in FIG. 7, tubing is installed at each inlet and outlet, and a sample solution containing particles to be separated at a constant pressure by a syringe pump or the like is injected through the installed tubing into the main channel inlet . On the other hand, another syringe pump can inject the solvent liquid through the tubing to the side channel inlet at a constant pressure. When the flow rate of the sample liquid is Qm and the flow rate of the solvent liquid is Qs, the sample liquid and the solvent liquid are injected so that Qs / Qm is 5 or more in one embodiment, so that the sample liquid flows near the main flow wall surface The alignment is maintained so that the cut-off layer is formed. Samples separated in size from each outlet through each branch channel can be collected in separate containers as shown in Fig.

It should be understood, however, that the above-described methods of working the channel, and the respective numerical values associated with the channel and the substrate are merely exemplary and are not intended to limit the method or form of manufacture of the microfluidic chip filtering device according to the embodiments.

On the other hand, the present inventors fabricated a designed microfluidic chip and performed separation experiments using model particles to confirm the degree of recovery by measuring the recovery and purity of separation efficiency.

FIGS. 8A and 8B are graphs showing recovery rates and purity, respectively, for separation by size of three dispersed particles by a conventional hydrodynamic filtration method. FIG.

Specifically, after the microfluidic chip as described above with reference to FIGS. 5 and 6 is constructed, separation of three dispersed particles is performed by applying the conventional hydrodynamic filtration conditions described above with reference to FIG. 5A, 8b. Solvent solutions were prepared by dissolving 0.15% (w / v) of Triton X-100, a nonionic surfactant, and 10 mM of potassium chloride (KCl) as an electrolyte, in a second distilled water to prevent aggregation between particles. It was confirmed that the ion concentration thereof was 10 mM. In addition, sample liquids were prepared by dispersing spherical polystyrene latex particles having diameters (D) of 1, 3, and 6 μm, respectively, in a solvent solution under the condition that three kinds of latex particles had the same number.

The sample liquid and the solvent liquid prepared as described above are injected into the main channel and the side channel, respectively. Then, the particles separated and discharged into the three outlets are received in the respective containers, and a certain volume is taken therefrom. Were calculated by a fluorescence microscope and an imaging program.

At this time, the recovery rate and purity are measures for quantitatively determining the separation efficiency. The recovery rate is defined as [the number of particles to be separated collected at a particular exit] divided by [the total number of particles to be separated from the sample collected at all the outlets]. The purity is defined as [the number of particles to be separated] divided by [the total number of particles in the sample collected at each outlet].

9A and 9B are graphs respectively showing recovery rates and purity for separation of three dispersed particles according to size of a microfluidic chip filtration method according to an embodiment.

In this Example, a water-soluble solvent liquid in which only 0.15% (w / v) of Triton X-100 was dissolved in the second distilled water and potassium chloride (KCl) was not administered was prepared. Its ion concentration was 4 × 10 -4 mM Respectively. On the other hand, the sample solution was prepared by dissolving 10 mM of potassium chloride (KCl) in the same manner as in the test example of FIGS. 8A and 8B, and the particles were dispersed in the prepared water-soluble solvent. The kind and diameter of the particles were also the same as those in FIGS. 8A and 8B. The sample liquid and the solvent liquid prepared as described above are injected into the main channel and the side channel, respectively. Then, the particles separated and discharged into the three outlets are received in the respective containers, and a certain volume is taken therefrom. Was calculated.

Comparing Figures 8A and 9A, it can be seen that the recovery rate obtained by the method and apparatus according to the embodiment of the present invention is higher for all diameter particles. 8B and 9B, it can be seen that the purity obtained by the method and apparatus according to the embodiment of the present invention is higher for all diameters of particles.

While the invention has been shown and described with reference to certain embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. However, it should be understood that such modifications are within the technical scope of the present invention. Accordingly, the true scope of the present invention should be determined by the technical idea of the appended claims.

Claims (18)

Injecting a sample solution containing particles and an electrolyte and having a first ion concentration into the main channel;
Injecting a solvent solution into the side channel connected to the first side of the main channel, the solvent solution having an electrolyte and a second ion concentration lower than the first ion concentration; And
And withdrawing the particles from the main channel with one or more branch channels connected to a second side of the main channel different from the first side by the solvent liquid.
The method according to claim 1,
And adjusting the thickness of the electric double layer formed on the wall surface of the main channel using the first ion concentration and the second ion concentration.
3. The method of claim 2,
Wherein adjusting the thickness of the electric double layer is configured to adjust the thickness of the electric double layer formed on the second side of the main channel and the wall surface of the branch channel using the first ion concentration.
The method according to claim 2 or 3,
Wherein adjusting the thickness of the electric double layer is configured to adjust the thickness of the electric double layer formed on the first side of the main channel using the second ion concentration.
The method according to claim 1,
Wherein the first ion concentration is 10 4 to 10 6 times the second ion concentration.
The method according to claim 1,
Wherein the first ion concentration is from 10 mM to 100 mM.
The method according to claim 1,
And the second ion concentration is 10 -4 mM to 10 -1 mM.
The method according to claim 1,
Wherein the electrolyte comprises a cation and an anion dissociated at a ratio of 1: 1.
A main channel configured to flow a sample liquid including particles and an electrolyte;
A side channel connected to the first side of the main channel, the side channel concentrating the sample solution to the second side of the main channel by injecting a solvent solution containing the electrolyte; And
And one or more branch channels connected to a second side of the main channel and configured to allow the particles to escape from the main channel,
Wherein the sample liquid has a first ion concentration and the solvent liquid has a second ion concentration lower than the first ion concentration.
10. The method of claim 9,
And an electrical double layer formed on the wall surface of the main channel by ions generated by dissociation of the electrolyte and having a thickness determined by the first ion concentration and the second ion concentration.
11. The method of claim 10,
Wherein the electrical double layer comprises a layer formed on the second side of the main channel and a wall surface of the branch channel and the thickness being determined by the first ion concentration.
11. The method according to claim 9 or 10,
Wherein the electrical double layer further comprises a layer formed on the first side of the main channel and having a thickness determined by the second ion concentration.
10. The method of claim 9,
Wherein the first ion concentration is 10 4 to 10 6 times the second ion concentration.
10. The method of claim 9,
Wherein the first ion concentration is from 10 mM to 100 mM.
10. The method of claim 9,
And the second ion concentration is 10 -4 mM to 10 -1 mM.
10. The method of claim 9,
Wherein the electrolyte comprises a cation and an anion dissociated in a ratio of 1: 1.
10. The method of claim 9,
Wherein each of the main channel, the side channel, and the at least one branch channel has a shape in which the height of the channel is larger than the width.
A first substrate;
A main channel formed on the first substrate and configured to flow a sample solution including particles and an electrolyte; A side channel connected to the first side of the main channel, the side channel concentrating the sample solution to the second side of the main channel by injecting a solvent solution containing the electrolyte; And at least one branch channel connected to a second side of the main channel and configured to allow the particles to escape from the main channel; And
And a second substrate bonded to a surface of the first substrate on which the microfluidic chip filtering device is formed,
Wherein the sample liquid has a first ion concentration and the solvent liquid has a second ion concentration lower than the first ion concentration.
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FR2931141B1 (en) * 2008-05-13 2011-07-01 Commissariat Energie Atomique MICROFLUIDIC SYSTEM AND METHOD FOR THE SORTING OF AMAS FROM CELLS AND PREFERENCE FOR CONTINUOUS ENCAPSULATION THROUGH THEIR SORTING
KR101511569B1 (en) 2013-11-14 2015-04-14 포항공과대학교 산학협력단 Particle separation apparatus

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EP3699587A4 (en) * 2017-10-19 2021-07-14 TL Genomics Inc. Chip for cell classification
US11666915B2 (en) 2017-10-19 2023-06-06 Tl Genomics Inc. Cell classification chip
US11712694B2 (en) 2020-07-09 2023-08-01 Saudi Arabian Oil Company In-situ salinity and ionic concentration control for calcite coated microfluidic cell
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